This invention relates to controlling cellular immune/inflammatory responses, particularly phagocyte-mediated tissue injury and inflammation.
Circulating phagocytic white blood cells are an important component of the cellular acute inflammatory response. It is believed that a number of important biological functions such as chemotaxis, immune adherence (homotypic cell adhesion or aggregation), adhesion to endothelium, phagocytosis, antibody-dependent cellular cytotoxicity, superoxide, and lysosomal enzyme release are mediated by a family of leukocyte surface glycoprotein adhesion receptors known as .beta..sub.2 integrins or the CD11/CD18 complex. Arnaout et al., Blood 75:1037 (1990). Inherited deficiency of CD11/CD18 impairs leukocyte adhesion-dependent inflammatory functions and predisposes to life-threatening bacterial infections. Dana et al., J. Clin. Invest. 73:153 (1983); Arnaout et al., J. Clin. Invest. 74:1291 (1984).
The CD11/CD18 family consists of three heterodimeric surface glycoproteins, each with a distinct .alpha. subunit (CD11a, CD11b or CD11c) non-covalently associated with a common .beta. subunit (CD18). The divalent cations Ca.sup.+2 and Mg.sup.2+ are essential in the stabilization and function of the .alpha..beta. (CD11/CD18) complex.
The .beta.2 integrins are expressed only on leukocytes. While CD11a/CD18 (also known as LFA-1, TA-1) is expressed on all leukocytes, CD11b/CD18 and CD11c/CD18 (also known as LeuM5 or p150,95) are expressed primarily on monocytes, polymorphonuclear leukocytes, macrophages and natural killer cells CD11c/CD18 is also expressed on certain lymphocytes. Arnaout, Blood 75:1037 (1990).
CD11a/CD18, and not CD11b/CD18 or CD11c/CD18, is expressed on B- and T-lymphocytes; accordingly CD11a/CD18 plays a role in mitogen-, antigen-, and alloantigen- induced proliferation, T-cell-mediated cytotoxicity, lymphocyte aggregation, and Ig production. In contrast, all three CD11/CD18 molecules are important for monocyte/macrophage and granulocyte adhesion-dependent functions.
It is believed that CD11b/CD18 and CD11c/CD18 mediate enhanced adhesiveness of activated phagocytes through quantitative and qualitative changes in these proteins on the surface of activated cells. For example, in granulocytes, these proteins are translocated from intracellular storage pools present in secondary and tertiary granules. Arnaout et al., J. Clin. Invest. 74:1291 (1984); Arnaout et al., New Eng. J. Med. 312:457 (1985); Todd et al., J. Clin. Invest. 74:1280 (1984).
CD11b/CD18 is also known as complement receptor type 3 (CR3), Mol, Mac-1 or MAM. See, Arnaout et al., J. Clin. Invest. 72:171 (1983), and references cited therein; Dana et al., J. Immunol. 137:3259 (1986); Wallis et al., J. Immunol. 135:2323 (1985); Arnaout et al., New Eng. J. Med. 312:457 (1985); Dana et al., J. Clin. Invest. 73:153 (1984); and Beatty et al., J. Immunol. 131:2913 (1983). Like all .beta.2 integrins, CD11b/CD18 consists of two non-covalently associated subunits. Kishimoto et al., Cell 48:681 (1987); Law et al., EMBO J. 6:915 (1987); Arnaout et al. J. Clin. Invest. 72:171 (1983). The .alpha. subunit of CD11b/CD18 has an apparent molecular mass of 155-165 kD and associates non-covalently with a .beta. subunit, CD18, of apparent molecular mass 95 kD. Todd et al., Hybridoma 1:329 (1982).
Monoclonal antibodies have been used to identify at least two distinct functional domains of CD11b/CD18, one mediating homotypic and heterotypic adhesion and the other mediating binding to the complement C3 fragment (iC3b), the major C3 opsonin in vivo. Dana et al., J. Immunol. 137:3259 (1986).
Law et al., EMBO J. 6:915 (1987) and Kishimoto et al., Cell 48:681 (1987) disclose the nucleotide sequence of human CD18. Arnaout et al., J. Cell Biol. 106:2153 (1988); Corbi et al., J. Biol. Chem. 263:12403 (1988); and Hickstein et al., Proc. Nat'l. Acad. Sci. USA 86:275 (1989) disclose the nucleotide sequence of human CD11b. Larson et al., J. Cell. Biol. 108:703 (1989) disclose the nucleotide sequence of CD11a. Corbi et al., EMBO J. 6:4023 (1987) disclose the nucleotide sequence of CD11c.
Cosgrove et al. (Proc. Nat'l. Acad. Sci. USA 83:752, 1986) report a human genomic clone which produces "a molecule(s)" reactive with monoclonal antibodies to CD11b.
Sastre et al. (Proc. Nat'l. Acad. Sci. USA 83:5644, 1986) report a mouse genomic clone coding for an amino-terminal partial exon of murine CD11b. Pytela et al., EMBO J. 7:1371 (1988) report a cDNA sequence of murine CD11b.
Simpson et al., J. Clin. Invest. 81:624 (1988) disclose that a monoclonal antibody (904) directed to an adhesion-promoting domain of CD11b (Dana et al., J. Immunol. 137:3259, 1986) reduces the extent of cardiac damage in dogs associated with myocardial infarction, presumably by limiting reperfusion injury. Vedder et al. (J. Clin. Invest. 81:939, 1988) similarly found that a monoclonal antibody directed against CD18 subunit of CD11b/CD18 reduced organ injury and improved survival from hemorrhagic shock in rabbits. In animal models, anti-CD11/CD18 antibodies have been shown to have protective effects in shock, frostbite, burns, cerebral edema, onset of diabetes mellitus (Hutchings et al., Nature 348:639, 1990) and transplant rejection. Reviewed in Carlos et al., Immunol. Rev. 114:5 (1990).